Cannabinoid compositions and uses

ABSTRACT

An inhalable composition for use as a medicament in the treatment of a subject wherein said composition comprises:
         one or more cannabinoids or a pharmaceutically acceptable derivative or salt thereof;   a propellant;   a monohydric or polyhydric alcohol; and   a glycol and/or glycol ether, characterised in that the ratio of monohydric or polyhydric alcohol to glycol or glycol ether by weight is from 6:1 to 1:1,   wherein the composition is administered in the form of an aerosol having a fine particle fraction of 60% or more.

FIELD OF THE INVENTION

The present invention relates to cannabinoid compositions and usestherefor.

BACKGROUND

Cannabinoids have long been known for their therapeutic potential inpain relief, treatment of seizures, antiemesis et cetera. It is,however, a class of compounds whose usage has been associated with agreat deal of debate owing to its psychoactive effects. It was not untilthe discovery of cannabinoid receptors (CB1 and CB2) and the isolationof individual cannabinoids such as THC (tetrahydrocannabinol), CBD(cannabidiol), CBN (Cannabinol), and THCV (Tetrahydrocannabivarin), thatthe psychoactive effects could be attributed primarily to compounds(like THC) with high affinities to the receptor CB1. Furthermore, it hasbeen established that individual cannabinoids differ from one another intheir affinities to receptors and certain cannabinoids, such as CBD,behave as CB1/CB2 antagonists, thereby blocking some actions of theiragonists, such as THC.

With on-going research, therapeutic applications of cannabinoids arebecoming increasingly evident, resulting in legalisation of thesecompounds for medical purposes in a number of countries. The primarytargets of research in this field are being associated with safe, rapidand/or effective delivery of cannabinoids.

A number of ways of delivering cannabinoids are known in the art.

For example, US2012/0304990 teaches the use of heating to vaporise acannabis deposit. One drawback of this system is that there is only asmall temperature differential between the temperature at which thecannabis will vaporise (180° c. to 200° c.) and the temperature at whichtoxins are produced (230° c.).

A number of documents (for example WO03/055549, U.S. Pat. No. 6,509,005and WO2004/000290) disclose the use of a metered dose inhaler. Suchinhalers suffer from a number of drawbacks. Firstly, the meteringchamber is relatively small, generally less than 100 μl resulting indelivery of fairly concentrated doses. Also, such devices require usersto optimally co-ordinate actuation of the outlet valve and inhalation,failing which, dose delivery could be variable.

A further common mechanism is the simple spray which is disclosed, forexample, in WO02/064109 and US2006/135599 which are designed to providea sublingual or buccal spray. Such a spray is currently being marketedby GW Pharmaceuticals under the Sativex™ brand. These sprays suffer fromthe possibility of non-uniform drug dose delivery owing to the flushingaction of saliva. Further, they have a slower onset of action whencompared with pulmonary delivery.

SUMMARY OF THE INVENTION

The present invention provides compositions, devices, and methods fordelivering a cannabinoid composition for use as a medicament. In oneembodiment the cannabinoid composition is delivered to a subject in theform of an inhalable aerosol having a fine particle fraction of 60% ormore. In one embodiment, the subject is a subject in need of prophylaxisor treatment with a cannabinoid. In one embodiment, the subject suffersfrom a condition or disorder selected from the group consisting ofneuropathic pain, cannabis addiction, nausea, motion sickness,arthritis, and neurodegenerative disease. In one embodiment, theneurodegenerative disease is selected from the group consisting ofAlzheimer's, Parkinson's and multiple sclerosis. In one embodiment, theinvention provides methods of treating a subject suffering from acondition or disorder selected from any of the foregoing. In oneembodiment, the invention provides methods of ameliorating one or moresymptoms associated with the condition or disorder.

In one embodiment, the cannabinoid composition is delivered to thesubject through an inhaler. In one embodiment, the inhaler comprises ahousing; a reservoir within the housing, said reservoir containing aninhalable cannabinoid composition; a composition flow path from thereservoir and out of a composition outlet at an inhaling end of thehousing; and a non-metered breath operated outlet valve for controllingthe flow of the cannabinoid composition through the composition flowpath, the inhalable composition comprising a cannabinoid or apharmaceutically acceptable derivative or salt thereof, and an alcohol.The alcohol can be a monohydric or a polyhydric alcohol. In oneembodiment, the alcohol is a monohydric alcohol and the inhalablecomposition further comprises one or more of a glycol and a glycolether. In a further embodiment, the ratio of alcohol, which ispreferably a monohydric alcohol, to glycol or glycol ether by weight isfrom 6:1 to 1:1. In one embodiment, the inhalable composition comprisesor consists of one or more cannabinoids or pharmaceutically acceptablederivatives or salts thereof; a propellant; a monohydric alcohol; and aglycol and/or glycol ether in a weight ratio of monohydric alcohol toglycol/glycol ether of from 6:1 to 1:1.

In one embodiment, the inhaler further comprises an air flow path froman inlet spaced from the inhaling end of the inhaler to an air outlet atthe inhaling end, the air flow path being configured such that suctionon the inhaling end causes flow through the air flow path which causesthe breath operated valve to open, the air outlet being positionedadjacent to the composition outlet, such that air from the air outletimpinges on the composition leaving the composition outlet. In a furtherembodiment, there is a respective air flow outlet on either side of theinhalable composition outlet.

In a further embodiment, the outlet valve comprises a flexible diaphragmwithin the housing positioned so as to be influenced by the air flowingthrough the air flow path; and a valve element movable with thediaphragm and biased by a biasing force into a position in which itcloses the composition flow path, such that suction on the inhaling endcauses a flow through the air flow path providing a pressuredifferential across the diaphragm thereby lifting the valve elementagainst the biasing force to open the composition flow path; and whereinthe biasing force is arranged to close the composition flow path oncethe suction ceases.

In a further embodiment, the inhaler comprises a first air flow pathpartly defined by one side of the diaphragm, a second air flow pathpartly defined by the opposite side of the diaphragm, each flow pathhaving an opening at the outlet end, wherein the air flow paths arearranged such that suction at the outlet end results in a pressuredifferential across the diaphragm that moves the diaphragm and hencemoves the valve element against the biasing force to open thecomposition flow path.

In a further embodiment, at least a portion of the flow path is adeformable tube, and the outlet valve is provided by a clamping memberwhich pinches the deformable tube closed when no suction force isapplied to the inhaling end to close the composition flow path andreleases the tube to open the composition flow path when suction isapplied at the inhaling end.

In a further embodiment, the inhaler further comprises a refill valve incommunication with the reservoir via which the reservoir may berefilled. In one embodiment, the reservoir is pressurised. In a furtherembodiment, the inhalable composition further comprises a propellant. Inone embodiment, the propellant is a hydrofluorocarbon. In oneembodiment, the propellant is present in an amount from at least 60%w/w, based on the total weight of the composition. In a furtherembodiment, the size of the reservoir, the pressure within thereservoir, and the size of the composition flow path at its narrowestpoint are arranged so that, when the outlet valve is fully opened, thereservoir will discharge in less than 30 seconds.

In one embodiment, the inhaler is configured to eject the inhalablecomposition therefrom in the form of droplets, at least 99% vol of thedroplets having a diameter of less than 10 microns.

The invention also provides an inhalable composition comprising one ormore cannabinoids or pharmaceutically acceptable derivatives or saltsthereof; a propellant; a monohydric or polyhydric alcohol; and a glycoland/or glycol ether, present in a weight ratio of monohydric orpolyhydric alcohol to glycol/glycol ether of from 6:1 to 1:1. In apreferred embodiment the alcohol is a monohydric alcohol. In oneembodiment, the one or more cannabinoids is selected fromtetrahydrocannabinol (THC), in particular(−)-trans-Δ9-tetrahydrocannabinol (also known as dronabinol),cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV),cannabigerol (CBG), cannabidivarin (CBDV), cannabichromene (CBC), andthe synthetic cannabinoid nabilone. In one embodiment, the one or morecannabinoids or pharmaceutically acceptable derivatives or salts thereofis present in an amount of from 0.01 to 15% w/w based on the totalweight of the composition. In one embodiment, the ratio of monohydricalcohol to glycol or glycol ether by weight is from 5:1 to 1.2:1. Theratio of monohydric alcohol to glycol or glycol ether by weight may beless than 5:1, or 4.5:1 or less, or 3:1 or less, or 1.5:1 or more, or2:1 or more. For example, the ratio may be from 4.5:1 to 1.5:1, or from3:1 to 2:1. In one embodiment, the glycol and/or glycol ether isselected from the group consisting of propylene glycol, polypropyleneglycol, polyethylene glycol (PEG), and combinations of two or morethereof. In one embodiment, the glycol and/or glycol ether is propyleneglycol and the composition comprises from 0.01 to 5% w/w or from 0.1 to2% w/w propylene glycol, based on the total weight of the composition.In one embodiment, the monohydric alcohol is ethanol. In one embodiment,the ethanol is present in an amount from 0.5 to 4% w/w, based on thetotal weight of the composition.

In one embodiment, the composition further comprises a human TAS2Rbitter taste receptor agonist, preferably wherein the human TAS2R bittertaste receptor agonist is saccharin. In one embodiment, the compositionfurther comprises saccharin in an amount by weight from 0.001% w/w to0.1% w/w. In one embodiment, the composition further comprises a flavourcomponent, preferably selected from peppermint oil, aniseed, chocolate,coco, menthol and/or vanillin. In one embodiment, the compositioncomprises up to 0.1% w/w menthol, based on the total weight of thecomposition.

The invention also provides a pressurised container containing acannabinoid composition for use according to the invention. In oneembodiment, the container is pressurised to a pressure of from 3×10⁵ Pato 1.5×10⁷ Pa.

The invention also provides a method of manufacturing a cannabinoidcomposition for use according to the invention, the method comprisingpreparing a pre-mixture comprising a monohydric or polyhydric alcoholand a glycol or glycol ether, and optionally a TAS2R taste receptoragonist and/or flavouring component, wherein the ratio of monohydric orpolyhydric alcohol to glycol or glycol ether by weight is from 6:1 to1:1; adding one or more cannabinoids or pharmaceutically acceptablederivatives or salts thereof, to the pre-mixture to obtain acannabinoid-containing mixture; and adding a propellant to thecannabinoid-containing mixture. In a preferred embodiment the alcohol isa monohydric alcohol. In one embodiment, the composition comprises aTAS2R taste receptor agonist and/or flavouring component, and whereinthe monohydric or polyhydric alcohol and glycol or glycol ether arecombined before the TAS2R taste receptor agonist and/or flavouringcomponent are added.

The invention also provides an inhaler comprising a cannabinoidcomposition for use according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded perspective view of an inhaler;

FIG. 2 is a schematic axial cross-section through the outlet end of theinhaler in the plane containing an air flow path and with the vaneremoved for clarity;

FIG. 3 is a perspective view of the outlet end of the inhaler with thecover, vane and diaphragm removed to show the air flow paths;

FIG. 4 is a perspective view of the outlet end of the inhaler;

FIG. 5 is a plan view of the inhaler;

FIG. 6 is a full cross-section of the inhaler;

FIG. 6A is a cross-section through line 6A-6A in FIG. 6; and

FIGS. 7-9 are cross-sectional views of an inhaler of a second example invarious orientations.

DETAILED DESCRIPTION

The present invention is particularly concerned with an aerosolcomposition for cannabinoids. The invention provides inhalablecannabinoid compositions, devices for their administration, and methodsof use. In accordance with the methods and compositions of theinvention, the cannabinoids are delivered directly to the lungs wherethey are efficiently absorbed into the systemic circulation, resultingin a rapid onset of therapeutic action. The rapid onset of therapeuticaction achievable through the compositions and methods of the inventionoffers an advantage over prior cannabinoid delivery methods such asoral, sublingual or suppository delivery, which generally involve slowersystemic absorption. The compositions and methods of the invention alsooffer the ability to deliver cannabinoids via inhalation at lowertemperatures than is possible via the inhalation of cannabinoidsvaporised from a cannabis plant surface. In addition, the compositionsof the invention administered according to the methods described hereinare expected to provide a more uniform and reliable drug absorptionprofile compared to oral, suppository or sublingual delivery methods.The compositions of the invention may also be administered in aconvenient and hygienic manner compared to prior art compositions anddelivery methods.

The term “cannabinoid” as used herein may encompass a chemical compoundthat activates any mammalian cannabinoid receptor, for example human CB₁receptor or human CB₂ receptor. As used herein a chemical compound thatactivates a mammalian cannabinoid receptor includes agonists of saidreceptor. The skilled person may readily determine whether a compound isa cannabinoid receptor agonist or activator using assays known in theart, for example using a suitable [³⁵S]GTPγS binding assay (see, forexample Griffin et al, Journal of Pharmacology and ExperimentalTherapeutics, 285(2), pp. 553-560, 1998). The cannabinoids may benaturally occurring (such as, for example, endocannabinoids orphytocannabinoids) or they may be synthetic. Synthetic cannabinoids mayinclude, for example, the classical cannabinoids structurally related toTHC, the non-classical cannabinoids (cannabimimetics) including theaminoalkyindoles, 1,5-diarylpyrazoles, quinolines andarylsulphonoamides, and eicosanoids related to the endocannabinoids.When a cannabinoid salt is used, it may be employed in the form of asolution. The one or more cannabinoids is preferably selected from theclassical cannabinoids, more preferably selected fromtetrahydrocannabinols (THC), preferably delta-9-tetrahydrocannabinol anddelta-8-tetrahydrocannabinol, more preferably(−)-(−)-trans-Δ⁹-tetrahydrocannabinol and trans-Δ⁸-tetrahydrocannabinol,cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV),cannabigerol (CBG), cannabidivarin (CBDV) and cannabichromene (CBC),cannabicyclol (CBL), cannabichromevarin (CBCV), cannabigerovarin (CBGVand cannabigerol monomethyl ether (CBGM). CBD and THC are particularlypreferred cannabinoids in the present invention. In a particularlypreferred embodiment, the composition comprises both CBD and THC. CBDtypically exhibits only a minimal psychoactive effect. CBD may also actas a potent antagonist to the CB1 receptor, thereby counteracting thepsychoactive effect of THC without altering its advantageous clinicaleffects. The compound “tetrahydrocannabinol” as referred to herein mayencompass(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol.The compound “cannabidiol” as referred to herein may encompass2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol.

Other cannabinoids suitable for use in the present invention areendocannabinoids, substances that naturally occur in the mammalian bodyand which activate one or more cannabinoid receptor. Preferablyendocannabinoids are selected from arachidonoylethanolamine (AEA),2-arachidonoylglycerol (2-AG), 2-arachidonyl glyceryl ether (noladinether), N-arachidonoyl dopamine (NADA), virodhamine (OAE) andlysophosphatidylinositol (LPI).

Synthetic cannabinoids suitable for use in the present invention includenabilone, rimonabant, JWH-018, JWH-073, CP-55940, dimethylheptylpyran,HU-210, HU-331, SR144528, WIN 55,212-2, JWH-133, levonantradol, andAM-2201.

Cannabinoid Inhaler Device

According to the present invention a cannabinoid inhaler comprises ahousing; a reservoir within the housing of inhalable compositioncomprising a cannabinoid or a pharmaceutically acceptable derivative orsalt thereof, and an alcohol; a composition flow path from the reservoirand out of a composition outlet at an inhaling end of the housing; and anon-metered breath operated outlet valve for controlling the flow ofinhalable composition through the composition flow path.

The use of a non-metered and breath operated valve provides a number ofadvantages over the prior art dispensers. As the valve is breathoperated, it can only be opened when a user is inhaling such that, atthe moment the valve opens to release the composition, there is anexisting flow of air into the lungs thereby facilitating the entrainmentof the composition into the lungs. Further, as the administration offormulation is unmetered, the user can self-titrate and can obtain adose (i.e. one fill of the device) over a number of inhalations (orpuffs) at a desired, comfortable pace. This can be done in a fewinhalations and potentially in a single inhalation if desired.

Thus, the present invention provides a cannabinoid inhaler which is easyto use and provides a way of obtaining a relatively consistent dose withminimal wastage for deep lung administration and rapid onset of clinicalactions as compared to a metered dose inhaler or spray.

The breath-operated valve may have a number of configurations. It may,for example, comprise an electronic flow sensor which detects suction onthe inhaling end and activates a solenoid to open the outlet valve.Alternatively, the valve may be a heater which selectively vaporises aproportion of a viscous composition, with the reservoir being configuredto replenish the viscous composition in the vicinity of the heater. As afurther example, the valve may take the form of a Venturi nozzle whichgenerates a suction force when a user inhales. The suction force maydirectly remove the composition from the housing, or the valve mayfurther comprise a closure element which is opened by the suction force.

The important consideration for the outlet valve is that it is able toselectively allow the dispensing of composition in response to a userinhaling from the inhaler.

However, preferably, the inhaler further comprises an air flow path froman inlet spaced from the inhaling end to an air outlet at the inhalingend, the air flow path being configured such that suction on theinhaling end causes flow through the air flow path which causes thebreath operated valve to open, the air outlet being positioned adjacentto the composition outlet, such that air from the air outlet impinges onthe composition leaving the composition outlet.

The provision of an air flow path which both operates the breathoperated valve and also impinges on the composition outlet provides adual benefit in opening the valve and having a beneficial effect on theparticle size, as the impinging air breaks up larger droplets of thecomposition thereby significantly decreasing the mean particle size. Ifan air flow outlet is provided on either side of the inhalablecomposition outlet, this effect is enhanced and any deflection of thecomposition plume caused by a single air outlet is avoided.

The breath-operated valve is preferably provided by a flexible diaphragmwithin the housing and being positioned so as to be influenced by theair flowing through the air flow path; a valve element movable with thediaphragm and biased by a biasing force into a position in which itcloses the composition flow path; wherein suction on the inhaling endcauses a flow through the air flow path providing a pressuredifferential across the diaphragm thereby lifting the valve elementagainst the biasing force to open the composition flow path; and whereinthe biasing force is arranged to close the composition flow path oncethe suction ceases.

The use of a flexible diaphragm is beneficial as it can provide arelatively large surface area so that it is able to open the valve evenwith a relatively low flow rate. This allows the inhaler to open at arelatively low flow rate as compared to a standard metered dose inhalerwhich is useful for patients who find it difficult to inhale deeply.

Preferably, the inhaler further comprises a first air flow path partlydefined by one side of the diaphragm, a second air flow path partlydefined by the opposite side of the diaphragm, each flow path having anopening at the outlet end, wherein the air flow paths are arranged suchthat suction at the outlet end results in a pressure differential acrossthe diaphragm that moves the diaphragm and hence moves the valve elementagainst the biasing force to open the composition flow path. Thepresence of the first and second air flow paths minimises further thesuction required to open the valve.

Preferably, at least a portion of the flow path is a deformable tube,and the outlet valve is provided by a clamping member which pinches thedeformable tube closed when no suction force is applied to the inhalingend to close the composition flow path and releases the tube to open thecomposition flow path when suction is applied at the inhaling end. Thedeformable tube provides a simple mechanism for the breath-operatedvalve which operates particularly well with the flexible diaphragm toprovide a simple, reliable and easy to operate breath-operated valve.

The inhaler may be designed for a single use. However, preferably, theinhaler has a refill valve in communication with the reservoir via whichthe reservoir may be refilled.

The reservoir may be at atmospheric pressure. However, it is preferablypressurised as this pressure can provide the motive force to expel thecomposition from the reservoir. The reservoir may be pressurised byusing a compressed gas. However, preferably, the formulation furthercomprises a propellant as this allows the pressure in the reservoir tobe substantially maintained as the composition is dispensed.

Preferably, the pressure within the reservoir and the size of thecomposition flow path at its narrowest point are arranged so that, whenthe outlet valve is fully opened, the reservoir will discharge in lessthan 30 seconds.

Such a reservoir is an optimal size for cannabinoid delivery as itallows a user to obtain a dose over 8 to 10 puffs, on average. However,the inhaler is not so large that it contains a dose which is likely tobe harmful to either the authorised patient or some third party. In viewof this, it is not necessary to provide a lock-out mechanism on theinhaler itself.

Preferably, the inhaler is configured to eject inhalable compositiontherefrom in the form of droplets, at least some of which have adiameter of 10 μm or less, and preferably at least 99% vol of thedroplets have a diameter of less than 10 μm.

This relatively small particle size is ideal for pulmonary delivery, andco-operates particularly well with a breath-operated valve to ensurethat there is a flow of relatively small particle size delivered intothe pre-existing suction air stream ensuring even more reliable andrepeatable delivery deep into the lungs.

The inhaler as described herein may comprise the inhalable compositionas described herein.

An example of an inhaler in accordance with the present invention willnow be described with reference to the accompanying drawings

FIG. 1 is an exploded perspective view of an inhaler;

FIG. 2 is a schematic axial cross-section through the outlet end of theinhaler in the plane containing an air flow path and with the vaneremoved for clarity;

FIG. 3 is a perspective view of the outlet end of the inhaler with thecover, vane and diaphragm removed to show the air flow paths;

FIG. 4 is a perspective view of the outlet end of the inhaler;

FIG. 5 is a plan view of the inhaler;

FIG. 6 is a full cross-section of the inhaler;

FIG. 6A is a cross-section through line 6A-6A in FIG. 6; and

FIGS. 7-9 are cross-sectional views of an inhaler of a second example invarious orientations.

The inhaler described below is based on that disclosed in WO2010/073018. For further details of the device and its refill mechanism,reference is made to WO 2009/001078 and WO 2011/095781.

As shown in FIG. 1, the inhaler comprises a housing 1 which is broadlydivided into two parts. The distal part is a reservoir 2 and theproximal part is the breath-activated valve mechanism 3. At the refillend 4 is a refill valve 5 allowing the reservoir to be filled. Thereservoir may contain a wick 6 as shown in FIG. 6 and disclosed in WO2011/107737. At the opposite end is the outlet end 7 which will bedescribed in more detail below.

An elastomeric insert 10 (described in greater detail in GB 1305496.0)in the form of a tube open at both ends is inserted from the distal end.This insert 10 is normally pinched closed by a valve element 11 which isbiased downwardly by a spring 12. This pinch closed valve mechanism isdescribed in greater detail in WO 2011/015825.

The valve element 11 is part of a vane 13 which extends along most ofthe outlet end of the inhaler. The vane 13 is surrounded by a diaphragm14 which extends across the entire lower face of the vane 13, with theexception of the orifice through which the valve element 11 projects.This valve element is sealed around its periphery to the surroundinghousing. At the distal end of the diaphragm 14 is a kink 15 whichprovides some degree of freedom for the vane 13 to move up and down. Theopposite end of the vane 13 is integral with a surrounding frame that isfitted into the housing such that there is a direct connection betweenthe frame and vane to provide a hinge about which the vane pivots.

A mechanism for opening the valve element 11 against the action of thespring 12 will now be described.

This is achieved by first 16 and second 17 air flow paths as best shownin FIG. 2. The first flow path 16 is above the diaphragm 14 with the topof the flow path being formed by housing part 18 which is fixed to thehousing 1 once the valve elements are in place. The first air flow pathis essentially provided by a first air flow path outlet orifice 19 whichleads into the space occupied by the vane 13 above the diaphragm 14.This flow path has no other orifices.

The second air flow path 17 is below the diaphragm 14 and is defined bya pair of second air flow path inlet orifices 20 (only one of which isshown in FIG. 2). In the present example, the second air flow path isactually defined by two separate paths which extend from the inletorifices 20 along passages 17 which are defined by the housing 1 on thelower surface and the diaphragm 11 at its upper surface and whichextends alongside the second portion 9 of the reservoir to the outletend terminating at a pair of second air flow path outlet orifices 21which are smaller than the corresponding inlet orifices 20 and aredirected towards it to break up the particle size of the compositionplume as described in greater detail in GB 1215282.3. The flow throughthe second air flow path is depicted by arrows in the lower part of FIG.2 and in FIG. 3. Baffles 22 are provided along the second air flow path17 to increase the flow resistance in this path.

As a user sucks on the outlet end 7, air is sucked out of the first flowpath outlet orifice 19 thereby lowering the pressure in the first airflow path 16. At the same time, air is drawn in through the second flowpath air inlet orifices 20. As these are larger than the second flowpath outlet orifices 21, a choking effect aided by the baffles 22effectively causes pressure to increase in the second air flow path. Acombination of a reduced pressure above the vane and a raised pressurebelow the vane 13 causes the vane to be moved upwardly deforming thediaphragm 14 and raising the valve element against the action of thespring 12. When a user stops sucking on the outlet end 7, the pressureabove and below the diaphragm 14 equalises and the spring 12 returns thevalve element 11 to a position in which it pinches the insert 10 closed.

A second example of an inhaler is shown in FIGS. 7 to 9. This isdescribed in greater detail in GB 1305494.5. In place of the wick 6,this example is provided with a tube 30 having an internal bore 31leading to the insert 10 at the opposite end of tube 31.

At the inlet end 32 of the tube 30, the bore 31 has an inlet 33 which issupported by a support 34 so that the inlet end 32, and preferably theinlet 33 of the bore 31 is on the main axis X of the housing 1 as shownin FIG. 7.

It will be appreciated from the drawings that the shape of the reservoiris complex. The right hand portion has a generally cylindricalconfiguration occupying the majority of the diameter of the device whilethe left hand portion of the reservoir may just be the internal bore 31of the tube, or there may be a portion of the reservoir on either sideof this tube. Further, in the right hand portion, the volume of thereservoir is reduced by the inlet end portion of the tube 30, thesupport 34, and the refill valve assembly 5. Thus, while the volume ofthe reservoir 4 can be determined by measuring these components, it maybe simpler to determine this experimentally.

The operation of the device will now be described with reference toFIGS. 7 to 9.

When a user sucks on the outlet end 7, the outlet valve 3 opens aspreviously described. Provided that the inlet 33 of the bore 31 is belowthe level L of the liquid in the reservoir, the liquid will travel alongthe bore 31 and will be atomised downstream of the outlet valve element11 to create a plume for inhalation. FIGS. 7 to 9 show the centroid C ofa body of liquid filling the reservoir 4. The inlet 33 of the bore 31 isin the vicinity of the centroid. In this specific example shown in FIG.1, it is displaced by 1.3 mm from the centroid C towards the refill end4. In the horizontal orientation shown in FIG. 1, all of the liquidabove the level L which represents approximately 50% of the total liquidin the reservoir can be inhaled from the inhaler. When the inhaler is inthe tip-down configuration shown in FIG. 2, as the inlet 33 is displacedfrom the centroid C as described above, slightly more liquid isavailable than it is in FIG. 1. Conversely, in the tip-up configuration,slightly less liquid is available for inhalation. In a differentarrangement, the inlet 33 is at the centroid C, so that there isessentially no variation in dispensing between the three positions. Thecurrent preference is for a slight displacement of the inlet 33 towardsthe refill end from the centroid C as shown as this causes slightly moreliquid to be dispensed in the more common tip-down orientation.

Once the cigarette reaches the liquid level position L shown in FIGS. 7to 9 with the reservoir approximately half full, no further liquid canbe inhaled and the inhaler then needs to be refilled via the refillvalve 5.

Pressurized Container

In a further aspect, the present invention provides a pressurisedcontainer containing the composition as described herein. Thepressurised container may be used to release a gaseous flow of thecomposition to a user. For example, the pressurised container may beprovided with means for delivering the contents of the container to thelungs of a user. Such means may take the form of a button, trigger orbreath-activated mechanism. The pressurised container may be used todeliver an unmetered dose of cannabinoid to the user. This may beadvantageous over prior art methods of cannabis replacement therapy,such as conventional inhalers, nasal sprays, lozenges and patchescurrently on the market, because it can allow autonomy in cannabinoidreplacement regulation, where the user can regulate the amount ofcompositional cannabinoid he or she wishes to inhale.

The pressurised container of the present invention may be used torelease the composition to a user without the need for a separate sourceof energy. For example, the composition may be released withoutrequiring the heating of substrates, combustion of material or a batterypowered electric current. As discussed above, this can result in areduction in the levels of harmful by-products delivered to a user.

The pressurised container of the present invention may take the form ofa pressurised canister, for example, a pressurised aluminium canister.The canister may be fully recyclable and/or reusable. The canister maybe refilled as required by a vending machine or a larger containercontaining the desired composition under a high pressure gradient. Inone embodiment, the canister is an AW5052 aluminium canister.

The pressurised container may be capable of dispensing the compositionas a mixture of aerosolised droplets. The mixture may have theappearance of a vapour or smoke.

The pressurised container may be pressurised to a pressure of from 3×10⁵Pa to 1.5×10⁷ Pa, preferably from 5×10⁵ Pa to 2×10⁶ Pa, more preferablyfrom 5.5×10⁵ Pa to 1×10⁶ Pa, even more preferably at about 6×10⁵ Pa.

Inhalable Cannabinoid Compositions

The compositions of the invention comprise one or more cannabinoids orpharmaceutically acceptable derivatives or salts thereof, a propellant,an alcohol, and a glycol and/or glycol ether. The alcohol may be amonohydric alcohol or a polyhydric alcohol, and is preferably amonohydric alcohol. Monohydric alcohol has a lower viscosity than aglycol or glycol ether. Accordingly, the composition is able to formdroplets of a smaller diameter in comparison to compositions in whichthe monohydric alcohol is not present. The present inventors havesurprisingly found that a specific ratio of monohydric alcohol to glycolor glycol ether results in a composition with a desired combination ofboth long term stability (for example the composition remains as asingle phase for at least a week at a temperature of 2-40° C.) and smalldroplet size. In a preferred embodiment, the ratio of monohydricalcohol:glycol or glycol ether by weight is from 6:1 to 1:1.

The composition preferably comprises from 0.01 to 15 w/w of the one ormore cannabinoids or pharmaceutically acceptable derivatives or saltsthereof based on the total weight of the composition, more preferablyfrom 0.01 to 10% w/w, even more preferably from 0.1 to 8% w/w, stilleven more preferably from 1 to 5% w/w. The composition preferablycomprises greater than 3% w/w of the one or more cannabinoids orpharmaceutically acceptable derivatives or salts thereof based on thetotal weight of the composition, more preferably greater than 4% w/w,even more preferably greater than 5% w/w.

In one embodiment, the invention provides an inhalable compositioncomprising:

-   -   one or more cannabinoids or pharmaceutically acceptable        derivatives or salts thereof;    -   a propellant;    -   an alcohol; and    -   a glycol and/or glycol ether, characterised in that the ratio of        alcohol:glycol or glycol ether by weight is from 6:1 to 1:1.

In one embodiment, the alcohol is a monohydric alcohol. Preferably themonohydric alcohol is ethanol. Ethanol has a particularly low viscosityin comparison to a glycol or glycol ether, and is therefore particularlyeffective at enabling the composition to form droplets of smalldiameter. In addition, ethanol is cheap, relatively non-harmful andreadily available. Preferably the composition comprises from 0.5 to 4%w/w ethanol, preferably from 0.75 to 3.5% w/w, more preferably from 1 to3% w/w based on the total weight of the composition. Preferably thecomposition comprises less than 2% w/w ethanol, more preferably 1.5% w/wor less ethanol.

In one embodiment, the present invention provides a compositioncomprising:

-   -   one or more cannabinoids or pharmaceutically acceptable        derivatives or salts thereof;    -   a monohydric alcohol; and    -   a glycol and/or glycol ether, characterised in that the ratio of        monohydric alcohol:glycol or glycol ether by weight is from 6:1        to 1:1.

In accordance with the methods and compositions of the invention, theglycol and/or glycol ether may aid the dissolution of the one or morecannabinoids or pharmaceutically acceptable derivatives or salts thereofin the composition. This avoids the presence of precipitates ofcannabinoids (or other additives such as saccharin, if present) in thecomposition, which could cause irritation when delivered to a user. Inaddition, the presence of glycol or glycol ether reduces the degradationof the cannabinoids that may occur over time, thereby increasing thelong-term stability or “shelf life” of the composition.

The glycol and/or glycol ether may be selected from propylene glycol,polypropylene glycol and polyethylene glycol (PEG), or combinations oftwo or more thereof. Suitably polyethylene glycols may have a molecularmass of less than 20,000 g/mol. An example of a suitable polyethyleneglycol is PEG 400. Preferably the glycol or glycol ether is propyleneglycol. Propylene glycol provides the composition with a particularlydesirable droplet size profile and provides enhanced solvation ofexcipients and reduces degradation of excipients. Preferably thecomposition comprises from 0.01 to 5% w/w propylene glycol, morepreferably from 0.1 to 3% w/w, even more preferably from 0.3 to 2% w/w.The composition preferably comprises at least 0.5% w/w propylene glycol,more preferably at least 0.8% w/w, even more preferably at least 1% w/w.

Preferably the composition further comprises a human TAS2R bitter tastereceptor agonist. The use of a human TAS2R bitter taste receptor agonistinduces bronchodilation, resulting in a reduction in the levels ofdelivery-related coughing. Accordingly, a user is more able to toleratethe composition since it causes very little irritation.

The human TAS2R bitter taste receptor agonist may be a naturallyoccurring compound or a synthetic compound. Examples of suitablenaturally-occurring compounds include Absinthin, Aloin, Amarogentin,Andrographolide, Arborescin, Arglabin, Artemorin, Camphor, Cascarillin,Cnicin, Crispolide, Ethylpyrazine, Falcarindiol, Helicin, Humuloneisomers, Limonin, Noscapine Papaverine, Parthenolide, Quassin, Sinigrin,and Thiamine. Examples of suitable synthetic compounds includeAcesulfame K, Benzoin, Carisoprodol, Chloroquine, Cromolyn, Dapsone,Denatonium benzoate, Dimethyl thioformamide, Diphenhydramine,Divinylsulfoxide, Famotidine, Saccharin, Sodium benzoate, and Sodiumcyclamate.

Preferably the human TAS2R bitter taste receptor agonist is saccharin.Saccharin is particularly effective as a human TAS2R bitter tastereceptor agonist, may be readily dissolved in the composition, isreadily available and provides the composition with a desirable tasteprofile. Preferably the formulation comprises 0.001% w/w to 0.1% w/w,more preferably 0.003% w/w to 0.01% w/w and even more preferably 0.005%w/w to 0.008% w/w saccharin. Lower levels of saccharin result in acomposition with an unacceptable tolerability. Higher levels ofsaccharin result in an acceptable tolerability but are disfavoured sincesaccharin they may lead to precipitates of saccharin forming in thecomposition, which may cause irritation when the composition isadministered to a user or blockage when the composition is incorporatedinto an inhaler. Such weight percentages also provide the compositionwith an optimised taste profile.

The propellant may be a hydrofluorocarbon, preferably ahydrofluoroalkane, even more preferably 1,1,2,2-tetrafluoroethane(HFA-134a) or 1,1,1,2,3,3-heptafluoropropane (HFC-227). Such compoundsare particularly effective as propellants and have no adverse effect onthe body.

The composition may comprise at least 60% w/w propellant, morepreferably at least 66% w/w, even more preferably from 90 to 99.5% w/w,even more preferably from 92 to 99% w/w, and even more preferably from96 to 99% w/w, based on the total weight of the composition. Thepropellant is preferably liquefied. Preferably the composition is aliquid. More preferably the composition is a pressurized liquid.

The composition may further comprise a flavour component. The use of aflavour component may mask the taste of the cannabinoids or derivativesor salts thereof. Suitable flavour components include the flavourcomponents typically added to inhalable products. Examples includecarotenoid products, alkenols, aldehydes, esters and delta-lactoneflavour constituents. Suitable carotenoid products include beta ionone,alpha ionone, beta-damascone, beta-damascenone, oxo-edulan I, oxo-edulanII, theaspirone, 4-oxo-beta-ionone, 3-oxo-alpha-ionone,dihydroactinodiolide, 4-oxoisophorone, safranal, beta-cyclocitral.Suitable alkenols include C₄ to C₁₀ alkenols, preferably C₅ to C₈alkenols. Specific examples include: cis-2-Penten-1-ol,cis-2-Hexen-1-ol, trans-2-Hexen-1-ol, trans-2-Hexen-1-ol,cis-3-Hexen-1-ol, trans-3-Hexen-1-ol, trans-2-Hepten-1-ol,cis-3-Hepten-1-ol, trans-3-Hepten-1-ol, cis-4-Hepten-1-ol,trans-2-Octen-1-ol, cis-3-Octen-1-ol, cis-5-Octen-1-ol, 1-Octen-3-ol and3-Octen-2-ol. Suitable aldehydes include benzaldehyde, glucose andcinnamaldehyde. Suitable esters include allyl hexanoate, benzyl acetate,bornyl acetate, butyl butyrate, ethyl butyrate, ethyl hexanoate, ethylcinnamate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyllactate, ethyl nonanoate, ethyl valerate, geranyl acetate, geranylbutyrate, isobutyl acetate, isobutyl formate, isoamyl acetate, isopropylacetate, linalyl acetate, linalyl butyrate, linalyl formate, methylacetate, methyl anthranilate, methyl benzoate, methyl benzyl acetate,methyl butyrate, methyl cinnamate, methyl pentanoate, methyl phenylacetate, methyl salicylate (oil of wintergreen), nonyl caprylate, octylacetate, octyl butyrate, amyl acetate (pentyl acetate), pentylhexanoate, pentyl pentanoate, propyl ethanoate, propyl isobutyrate,terpenyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethylbutyrate, ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyloctanoate, ethyl nonanoate, ethyl decanoate, ethyl dodecanoate, ethylmyristate, ethyl palmitate. Suitable delta-lactone flavour constituentsinclude delta-Hexalactone, delta-Octalactone, delta-Nonalactone,delta-Decalactone, delta-Undecalactone, delta-Dodecalactone, Massoialactone, Jasmine lactone and 6-Pentyl-alpha-pyrone. Flavour componentsmay serve to mask the taste of cannabinoids.

The flavour component is preferably menthol and/or vanillin. Thepresence of menthol, together with the saccharin, reduces the irritationexperienced by a user. Preferably the composition comprises up to 0.1%w/w menthol, preferably from 0.01% w/w to 0.08% w/w, more preferablyfrom 0.02% w/w to 0.06% w/w, even more preferably from 0.03% w/w to0.05% w/w, still even more preferably about 0.04% w/w, based on thetotal weight of the composition.

The compositions (including the propellant free composition) may besubstantially free of water, i.e. it may be that no water isdeliberately added to the compositions. The compositions may comprise 6%w/w or less water based on the total weight of the composition,typically 5% w/w or less, more typically 3% w/w or less, even moretypically 1% w/w or less, still even more typically 0.5% or less.

In a particularly preferred embodiment, the invention provides aninhalable composition comprising;

-   -   One or more cannabinoids,    -   A propellant comprising HF-134a,    -   Ethanol, and    -   Propylene glycol, characterized in that the ratio of ethanol to        propylene glycol by weight is from 6:1 to 1:1. Even more        preferably the one or more cannabinoids are selected from THC        and CBD, or a mixture thereof. Preferably each component of the        inhalable composition is present in the preferred proportions        disclosed herein. Even more preferably the one or more        cannabinoids are present from 0.01 to 15% w/w, the propellant is        present in at least 66% w/w, ethanol is present from 0.5 to 5%        w/w and the propylene glycol is present from 0.01 to 5% w/w. The        cumulative proportions of all components present in the        composition must add up to 100% w/w.

In a further embodiment of the invention, the inhalable compositionconsists essentially of the components described herein.

In a further embodiment of the invention, the inhalable compositionconsists of the components described herein.

Methods of Delivery

The present invention provides methods of delivering a cannabinoidcomposition to a subject by inhalation with an inhaler device. Incontrast to compositions of the prior art, the compositions of thepresent invention form small diameter droplets without the use oforganic acids, resulting in less irritation to the airways. Accordingly,the methods of the invention comprise methods for reducing discomfortand local irritation due to administering a cannabinoid composition byinhalation, the methods comprising administering a cannabinoidcomposition lacking organic acids.

The composition for use according to the present invention may bedelivered to a user via oral inhalation, specifically via pulmonaryadministration. Accordingly, it is effective for use in cannabisreplacement therapy or as an alternative to recreational smoking ofcannabis plant material, since it mimics some of the habitual aspects ofcannabis smoking.

In accordance with the methods of the invention, the cannabinoidcomposition comprises a monohydric alcohol and glycol or glycol ether ina ratio of from 6:1 to 1:1. As discussed above, the ratio of monohydricalcohol to glycol ether by weight results in a combination of bothstability and a desired droplet size profile. Preferably the ratio ofmonohydric alcohol:glycol or glycol ether by weight is from 5:1 to1.2:1.

In one embodiment, the cannabinoid composition is delivered via aconventional pressurised metered-dose inhaler (pMDI). According to thepresent invention the composition is delivered in the form of aerosoldroplets, some of which (such as, for example, at least 10% vol) have adiameter of less than 10 μm, typically less than 5 μm. (The term“diameter” as used herein is taken to mean the largest dimension of adroplet, and is measured using a Malvern Spraytec equipment, ifnecessary using a flow adaptor to ensure a total flow rate of at least15 L/min through the equipment.) Typically, the majority (such as, forexample, at least 50% vol) of the aerosol droplets have a diameter ofless than 5 μm, typically substantially all (such as, for example, atleast 90% vol, or even at least 95% vol) of the droplets have a diameterof less than 5 μm. Advantageously, when administered to a user, dropletswith a size of less than 10 μm tend to be deposited in the lungs, ratherthan, for example, the oropharynx. Accordingly, at least some (such as,for example, at least 10% w/w), typically substantially all (such as,for example, at least 90% w/w), of the cannabinoid enters thebloodstream via the pulmonary route, which results in rapid absorptionof the composition.

The composition may be delivered to the subject as an aerosol, whereinthe droplets have a size distribution wherein the fine particle fraction(FPF) is greater than 30%, preferably greater than 40%, more preferablygreater than 50%. In particular embodiments of the invention, the fineparticle fraction is 60% or more, preferably 61% or more, 62% or more,63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% ormore, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more,74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% ormore, 80% or more, 81% or more, 82% or more, 83% or more, 84% or more,85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% ormore, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more,96% or more, 97% or more, 98% or more, or 99% or more. FPF is thepercentage by weight of aerosol particles that have a diameter less than5 microns, where the term “diameter” as used herein is taken to mean thelargest dimension of a droplet, and is measured using a Malvern Spraytecequipment, if necessary using a flow adaptor to ensure a total flow rateof at least 15 L/min through the equipment.

Typically at least some (such as, for example, at least 10% vol) of thedroplets have a diameter of from 0.5 to 3 μm. Such droplets may bedeposited in the deep lung, and are therefore particularly able to enterthe blood stream via the pulmonary route. Typically at least some (suchas, for example, at least 10% vol) of the droplets have a diameter offrom 0.4 to 0.5 μm.

In another embodiment, the cannabinoid composition is delivered via aninhaler device described herein. In accordance with this embodiment, thedroplets may exhibit the following droplet diameter distribution:

Dv 90 of less than 20 μm, typically less than 10 μm, more typically lessthan 8, even more typically less than 6 μm, and/or

Dv 50 of less than 6 μm, typically less than 4 μm, more typically lessthan 3 μm, even more typically less than 1 μm, and/or

Dv 10 of less than 4 μm, typically less than 2 μm, more typically lessthan 1 μm, even more typically less than 0.5 μm.

The term “Dv10” as used herein refers to a droplet diameter that 10% volof the droplets in a composition have a smaller diameter than. The term“Dv50” as used herein refers to a droplet diameter that 50% vol of thedroplets in a composition have a smaller diameter than. The term “Dv90”as used herein refers to a droplet diameter that 90% vol of the dropletsin a composition have a smaller diameter than. Dv10, Dv50 and Dv90values may be determined using a Malvern Spraytec device.

Methods of Manufacture

In a further aspect the present invention provides a method ofmanufacturing the composition described herein, the method comprising:

-   -   preparing a pre-mixture comprising a monohydric or polyhydric        alcohol and a glycol or glycol ether, and optionally a TAS2R        taste receptor agonist and/or flavouring component, wherein the        ratio of monohydric or polyhydric alcohol:glycol or glycol ether        by weight is from 6:1 to 1:1;    -   adding one or more cannabinoids or pharmaceutically acceptable        derivatives or salts thereof, to the pre-mixture to obtain a        cannabinoid-containing mixture; and adding a propellant to the        cannabinoid-containing mixture. In a preferred embodiment the        alcohol is a monohydric alcohol.

If the cannabinoid is added before the alcohol and glycol or glycolether are combined, then precipitation of cannabinoid may occur.Likewise, if the composition comprises other components, such as aflavouring component or a TAS2R taste receptor agonist, then thesecomponents should be fully mixed into the pre-mixture before thecannabinoids are added in order to avoid precipitation of cannabinoids.In particular, it has been found that when the composition comprisesmenthol, the menthol should be fully dissolved into the pre-mixturebefore the cannabinoids is added in order to avoid precipitation of thecannabinoids.

When the composition is to include a TAS2R taste receptor agonist and/ora flavouring component, preferably the monohydric or polyhydric alcoholand glycol or glycol ether are combined before the TAS2R taste receptoragonist and/or a flavouring component are added. This avoidsprecipitation of the flavouring component or TAS2R taste receptoragonist.

Methods of Treatment

In a further aspect, the present invention provides a method of treatinga condition selected from: neuropathic pain, cannabis addiction, nausea,motion sickness, arthritis and neurodegenerative diseases such asAlzheimer's, Parkinson's and multiple sclerosis using the composition asdescribed herein.

The inhalable compositions described herein will now be furtherdescribed with reference to the following non-limiting examples.

Example 1

0.8 g of the following composition was prepared:

-   -   CBD: 9.185 mg    -   Δ⁹(−)-trans-THC: 0.415 mg    -   Ethanol: 18 mg    -   Propylene glycol: 15 mg    -   Menthol: 0.32 mg    -   Saccharin: 0.05 mg    -   HFA-134a: 0.77 g

THC and CBD were present in a ratio of 23:1 and account for 1.25% w/w ofthe composition. This composition is considered to be particularlyeffective for the treatment of neuropathic pain.

Example 2

0.8 g of the following composition was prepared:

-   -   Δ⁹(−)-trans-THC: 16 mg    -   CBD: 80 mg    -   Ethanol: 24 mg    -   Propylene Glycol: 16 mg    -   Menthol: 0.4 mg    -   Saccharin: 0.0504 mg    -   HFA-134a:0.664 g

The cannabinoids account for 12% of the formulation weight. Thiscomposition is considered to be particularly effective for the treatmentof nausea, motion sickness or other similar conditions.

Example 3

0.8 g of the following composition was prepared:

-   -   Δ⁹(−)-trans-THC: 0.25 mg    -   CBD: 5 mg    -   Ethanol: 16 mg    -   Propylene Glycol: 12 mg    -   Menthol: 0.32 mg    -   Saccharin: 0.0504 mg    -   HFA-134a: 0.766 g

The cannabinoids are in a ratio of 20:1. This composition is consideredto be particularly effective for the relief of the symptoms ofarthritis.

Example 4

0.8 g of the following composition was prepared:

-   -   CBD: 9 mg    -   Δ⁹(−)-trans-THC: 1 mg    -   Ethanol: 15 mg    -   Propylene glycol: 14.6 mg    -   Menthol: 0.35 mg    -   Saccharin: 0.05 mg    -   HFA-134a: 0.76 g

The cannabinoids CBD and THC account for 1.25% of the formulationweight. This composition is considered to be particularly effective forreducing the symptoms of Alzheimer's disease.

Example 5

The following composition was prepared:

-   -   Δ⁹(−)-trans-THC: 11.5 mg    -   Ethanol: 196 mg    -   Propylene glycol: 70 mg    -   Menthol: 8 mg    -   Saccharin: 0.7 mg    -   HFA-134a: 20.16 g

The formulation was inserted into a pinch valve simulated cigarette asdescribed herein. Five doses were emitted from the device and thedroplet size profile of each was measured using a Malvern Spraytecdevice as described herein. The fine particle fraction measured for thecomposition was 77%.

The present invention will now be further described with reference tothe following numbered clauses:

1. An inhalable composition comprising;one or more cannabinoids or pharmaceutically acceptable derivatives orsalts thereof,

-   -   a propellant;    -   a monohydric or polyhydric alcohol, and    -   a glycol and/or glycol ether, characterised in that the ratio of        monohydric or polyhydric alcohol to glycol or glycol either by        weight is from 6:1 to 1:1.        2. A composition comprising:        one or more cannabinoids or pharmaceutically acceptable        derivatives or salts thereof,    -   a monohydric alcohol; and    -   a glycol and/or glycol ether, characterised in that the ratio of        monohydric alcohol to glycol or glycol either by weight is from        6:1 to 1:1.

1.-44. (canceled)
 45. An inhalable composition for use as a medicamentin the treatment of a subject wherein said composition comprises: one ormore cannabinoids or a pharmaceutically acceptable derivative or saltthereof; at least 92% w/w of a propellant based on the total weight ofthe composition, wherein the propellant is a hydrofluorocarbon; from 0.5to 4% w/w ethanol based on the total weight of the composition; and from0.3 to 2% w/w propylene glycol based on the total weight of thecomposition, characterized in that the ratio of ethanol to propyleneglycol by weight is from 6:1 to 1.2:1, wherein the composition is to beadministered in the form of an aerosol having a fine particle fractionof 60% or more.
 46. The composition according to claim 45, wherein thefine particle fraction is 70% or more.
 47. The composition according toclaim 45, wherein the fine particle fraction is 75% or more.
 48. Thecomposition according to claim 45, wherein the one or more cannabinoidsis selected from tetrahydrocannabinol (THC), dronabinol, cannabidiol(CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabigerol(CBG), cannabidivarin (CBDV) and cannabichromene (CBC).
 49. Thecomposition according to claim 45, comprising from 0.01 to 15% w/w ofthe one or more cannabinoids or pharmaceutically acceptable derivativesor salts thereof based on the total weight of the composition.
 50. Thecomposition according to claim 45, wherein the alcohol is a monohydricalcohol, and the ratio of monohydric alcohol to glycol or glycol etherby weight is from 5:1 to 1.2:1.
 51. The composition according to claim45 wherein the composition comprises from 0.1 to 2% w/w propyleneglycol, based on the total weight of the composition.
 52. Thecomposition according to claim 45 wherein the composition furthercomprises a human TAS2R bitter taste receptor agonist.
 53. Thecomposition according to claim 52 wherein the human TAS2R bitter tastereceptor agonist is saccharin, and wherein the saccharin is present inthe composition in an amount by weight from 0.001% w/w to 0.1% w/w basedon the total weight of the composition.
 54. The composition according toclaim 45 further comprising a flavor component.
 55. The compositionaccording to claim 54 wherein the flavor component is menthol, andwherein the menthol is present in the composition in an amount up to0.1% w/w, based on the total weight of the composition.
 56. Thecomposition according to claim 54 wherein the flavor component isselected from at least one of peppermint oil, aniseed, chocolate, coco,and vanillin.
 57. A cannabinoid inhaler comprising: a housing; areservoir within the housing containing an inhalable compositioncomprising a cannabinoid or a pharmaceutically acceptable derivative orsalt thereof, and an alcohol; a composition flow path from the reservoirand out of a composition outlet at an inhaling end of the housing; and anon-metered breath operated outlet valve for controlling the flow ofinhalable composition through the composition flow path.
 58. The inhaleraccording to claim 57, wherein the breath operated inhaler furthercomprises an air flow path from an inlet spaced from the inhaling end ofthe inhaler to an air outlet at the inhaling end, the air flow pathbeing configured such that suction on the inhaling end causes flowthrough the air flow path which causes the breath operated valve toopen, the air outlet being positioned adjacent to the compositionoutlet, such that air from the air outlet impinges on the compositionleaving the composition outlet.
 59. The inhaler according to claim 58,wherein there is a respective air flow outlet on either side of theinhalable composition outlet.
 60. The inhaler according to claim 59,wherein the air flow outlets are directed towards a composition plumeemitted, in use, from the inhaler to break up the particle size of thecomposition plume.
 61. The inhaler according to claim 57, wherein theoutlet valve comprises: a flexible diaphragm within the housing andbeing positioned so as to be influenced by the air flowing through theair flow path; a valve element movable with the diaphragm and biased bya biasing force into a position in which it closes the composition flowpath; wherein suction on the inhaling end causes a flow through the airflow path providing a pressure differential across the diaphragm therebylifting the valve element against the biasing force to open thecomposition flow path; and wherein the biasing force is arranged toclose the composition flow path once the suction ceases.
 62. The inhaleraccording to claim 61, further comprising a first air flow path partlydefined by one side of the diaphragm, a second air flow path partlydefined by the opposite side of the diaphragm, each flow path having anopening at the outlet end, wherein the air flow paths are arranged suchthat suction at the outlet end results in a pressure differential acrossthe diaphragm that moves the diaphragm and hence moves the valve elementagainst the biasing force to open the composition flow path.
 63. Theinhaler according to claim 57, wherein at least a portion of the flowpath is a deformable tube, and the outlet valve is provided by aclamping member which pinches the deformable tube closed when no suctionforce is applied to the inhaling end to close the composition flow pathand releases the tube to open the composition flow path when suction isapplied at the inhaling end.
 64. The inhaler according to claim 57,wherein there is a single diaphragm and valve element.
 65. The inhaleraccording to claim 57, further comprising tube having an internal boreleading from an inlet on a main axis of the housing a reservoir outlet.